Artículo
CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic
Autor/es | van Dinther, Maarten
Cunningham, Kyle T. Singh, Shashi Prakash White, Madeleine P.J. Campion, Tiffany Ciancia, Claire van Veelen, Peter A. de Ru, Arnoud H. González Prieto, Román ![]() ![]() ![]() ![]() ![]() ![]() ![]() Mukundan, Ananya Maizels, Rick M. |
Departamento | Universidad de Sevilla. Departamento de Biología Celular |
Fecha de publicación | 2023 |
Fecha de depósito | 2024-02-14 |
Publicado en |
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Resumen | Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, down-modulates the host immune system through release of an immunosuppressive ... Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, down-modulates the host immune system through release of an immunosuppressive TGF-β mimic, TGM1, which is a divergent member of the CCP (Sushi) protein family. TGM1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGF-β receptors, acting on T cells to induce Foxp3+ regulatory T cells; however, the roles of domains 4 and 5 (D4/5) remain unknown. We noted that truncated TGM1, lacking D4/5, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not alter potency, suggesting that a physical linkage is required and that these domains do not deliver an independent signal. Coprecipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a coreceptor for TGM1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, to a greater degree than D1/2/3 alone, although some cell lines did not respond to TGM1. Ectopic expression of CD44 in nonresponding cells conferred responsiveness, while genetic depletion of CD44 abolished enhancement by D4/5 and ablated the ability of full-length TGM1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM1, to levels similar to those induced by D1/2/3. Hence, a parasite protein known to bind two host cytokine receptor subunits has evolved a third receptor specificity, which serves to raise the avidity and cell type–specific potency of TGF-β signaling in mammalian cells. |
Agencias financiadoras | Wellcome Trust. Reino Unido. Wellcome Centre for Integrative Parasitology. Reino Unido. National Institutes of Health (NIH). EE.UU. |
Identificador del proyecto | 219530
![]() 10411 ![]() AI153915 ![]() AI57069 ![]() |
Cita | van Dinther, M., Cunningham, K.T., Singh, S.P., White, M.P.J., Campion, T., Ciancia, C.,...,Maizels, R.M. (2023). CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic. Proceedings of the National Academy of Sciences of the United States of America, 120 (34), e2302370120. https://doi.org/10.1073/pnas.2302370120. |
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